Detecting small amounts of chemicals and substances in liquids have many applications in chemistry and biology. In medicine, for example, one can diagnose many diseases by detecting chemicals (sodium, nitrides, calcium, potassium, cardiac markers, etc.) and their concentrations in bodily fluids such as blood, urine, saliva etc. Detecting pathogens (Tuberculosis, Hepatitis, HIV viruses, etc.) in bodily fluids as well as in the environment is also area of active research and development.
Similarly measuring fluid viscosity has also great interest in industrial applications and medicine. The ability to gather data on viscosity gives manufacturer important information on how to design fluidic systems. Especially in microfluidic systems viscosity determines the pumpability of the fluids and pressure drops across the channels. For example, viscosity of inks is very crucial for inkjet printing systems. In automotive industry, it is necessary for lubricant manufacturers to know the viscosity of their lubricants developed for different parts of the car engine and hydraulic systems.
In medicine, blood viscosity and coagulation time measurements are used for the diagnosis of several diseases such as cardiovascular disorders, rheumatoid arthritis, and certain autoimmune diseases. Patients who use blood thinners need to monitor their blood viscosity and coagulation time continuously.
The sensor requirement for the above sensing areas can be addressed by vibrating mechanical structures. Especially microcantilevers find various applications based on advantages such as lower detection limits due to miniaturization, the ability of shape optimization of cantilevers, the ability to selectively place functionlized regions on the these cantilevers (also interchangeably called “microcantilevers”), and the possibility of working on large arrays which can be integrated with optics and electronics.
When these cantilevers are placed in liquid, the dynamics of the vibration (phase and amplitude) are influenced by the viscosity of the liquid and the mass accumulation on the cantilevers. By measuring the vibration phase and/or amplitude one can detect liquid viscosity and minute amounts of chemicals and substances that may exist in the liquid. Furthermore, the cantilevers can be set into oscillation using a feedback circuitry. In this case, frequency measurement can be used to monitor dynamic changes of the cantilever vibration.
To address the measurement needs for viscosity and mass, various methods have been proposed. Some of the disadvantages of these currently known types of sensors are; that they require electrical connections (also called electrical conductors) to couple the sensor to a detector, limited optical detection options, limitations to gas phase detection, sensors that use frail readout components (for example, Doppler vibrometry), readouts that can be affected by refractive index variations due to monitoring of the deflection, sensors with no immunity against environmental noise, and the inability to heat the cantilever/samples during sensing. Further, it is believed that current alternatives to parallel sensing are limited to laboratory use only. It is therefore desirable to have a fieldable, label-free demonstrator, which is missing due to the lack of various components including a suitable readout mechanism that can be utilized in an array setting, a package that would protect functionalized surfaces during shelf life, which usually requires handling of liquids, and an integrated approach that would allow disposal of certain components, whereas others remain for the next use (for example, disposable cartridges containing the MEMS sensor array).
One objective of this invention is to enable a MEMS sensor array having a sensor array that is miniaturized, highly selective, highly sensitive, parallel, label-free and/or portable. Such a sensor array will provide a valuable tool for point-of-care diagnostics, and chemical sensing with its capabilities of a single analyte or a multianalyte screening and data processing. In addition such a sensor can measure dynamic properties of bodily fluids such as viscosity, fluid damping and chemical changes of the liquid. It is a further objective of these sensor arrays to increase sensitivity and specificity to possibly increase the likelihood of early diagnosis as well as the suitability of treatment assistance, such as dosage advice. It is envisioned that this may lead to increased effectiveness of doctor-patient interaction and personalized guidance. It is believed that such systems that meet the demands of parallel, label-free, and highly selective sensing do not exist today as microsystem technologies and readout methods cannot meet expectations for various reasons including: robustness issues associated with functional surfaces and the lack of a truly integrated, array-compatible readout techniques. Alternatively, it is believed that microarray technologies can offer parallel and selective detection, but are not fieldable as they require expertise to run and maintain and require expensive infrastructure due to complex labeling and sensing methods. While many fieldable applications, such as pregnancy test kits or the glucose sensor exist, these applications are limited to one kind of species and lack parallel detection capability.
The sensor array platform is highly innovative and versatile and has inspired by the novel uses. For example, for the point-of-care diagnostics applications it is envisioned that a microsystem-based sensors or parallel sensor array (2 to 64 channels and more); can be used for various species for shifts in resonance frequency of an array of cantilevers will be monitored as an indication of mass accumulation. In this example, detection of frequency shifts will be carried out through a novel integrated optoelectronic chip. Sensitivity in the range of 0.1 to 1000 ng/ml with better than 25% reproducibility is aimed. In addition to resonance frequency, one can measure the phase difference between the drive signal and the micro-cantilever motion. Cantilevers can be functionalized with various chemicals and can be placed in different channels. The same fluid can be applied to the channels where the effect of the chemicals is measured on fluid viscosity by monitoring the phase difference between the excitation signal and mechanical vibration waveform of the cantilevers in the array. Typical sensitivity of 0.001 cps is possible to achieve using cantilevers.
Additionally, possible use of this invention include liquid phase detection of disease from body fluids (e.g., blood, serum, urine, or saliva), and a detector to detect pathogens that may exists in environmental water supplies. Additionally, it is believed that in an aqueous medium, the invention will allow parallel, fast, real-time monitoring of a large number of analytes (e.g., proteins, pathogens, and DNA strands) without any need for labeling, and, therefore, be ideal for the targets screening in drug discovery process, or as a promising alternative to current DNA and protein micro array chips. Using such a label-free device may decrease the number of preparation stages and shorten diagnosis time. It is proposed that one can investigate DNA sequences, successful results will be the positive detection of various mutations in human DNA (e.g., sickle cell anemia, -thallesemia) in parallel.
This invention demonstrates a highly parallel detection of changes in the dynamics of a cantilever array. The proposed sensor can be used for label-free detection of (bio/chem) agents as well as liquid viscosity measurement in a robust, miniaturized package using multiple disciplines including integrated photonics, VLSI, and Micro/Nano system technologies to develop a versatile sensor array with breakthrough performance.
Each sensor is typically located on a MEMS sensor array operates by monitoring the resonant frequency, amplitude and/or phase of the vibrating mechanical structures (also called cantilevers or microcantilevers). Output of a sensor is the change in resonant frequency, amplitude and/or phase in response to accumulated mass on the cantilever due to a specific binding event or changes in the viscosity of the liquid. The array of cantilevers may be actuated by an actuating means, for example, electromagnetic force means; piezoelectric force; electric force; electrostatic force means and combinations thereof. The most preferred actuating means is a single electro-coil that carries a superposed drive current waveform. Preferably optical feedback from a mechanism to sense light coupled with each sensor is used for detection of specific binding events and also for closed-loop control of the cantilevers at resonance. More preferably, damping can be tuned by closed-loop control electronics allowing sharp resonance peaks (high-Q) even in liquid media. In a preferred embodiment, frequency resolution is inherently higher compared to other read-out techniques such as the piezoresistive or capacitive methods.
Preferably, the MEMS chip contains the functionalization layer on magnetic structural layer (for example, Nickel). More preferably, the location on the cantilever of the functionalized layer can be chosen to maximize the resonant frequency shift per added unit mass or the phase shift. In a preferred embodiment, the novel structure of the cantilevers includes a diffraction grating in the form of simple slits and/or heating elements. The light reflected from the diffraction grating can be collected by optical fibers. In another arrangement, diffraction gratings can be omitted and flat surface of the cantilevers can be used to reflect the light. In this case, light can be still collected using optical fibers where the cantilever vibration determines the amount of light coupling to the optical fibers and hence, the photodetector output that the fibers are coupled represents the cantilever vibration amplitude and phase. The MEMS sensor array (also called a MEMS chip) is preferably envisioned to be disposable and replaceable in future products; for example, as a disposable cartridge containing a MEMS sensor array to be coupled with a detector apparatus containing an actuating means (also sometimes called an actuator). This preferred embodiment would leave the actuator and electronics layers intact for reuse. Preferably, the MEMS chip is a passive component with no electronic link (also called an electrical conductor) to the detector apparatus. In this preferred embodiment this will facilitate work in fluidic environments, since less isolation, coupling, and stiction issues need to be considered. Furthermore, the preferred embodiment includes the integration of electronics and optics coupled with a passive component to provide ease and flexibility of use compared to a direct integration of the MEMS layer with IC detection apparatus. Finally in a preferred embodiment, magnetic actuation can be carried out remotely through an external electromagnetic coil on the MEMS chip. It is believed that sensitivity levels achieved in mass measurements will directly be reflected by detection sensitivity of the analytes of interest. Additionally, the type of surface functionalization utilized on the cantilever surfaces will determine the field of application, e.g., Human Kappa Opioid receptor (HKOR) is utilized for the detection of narcotics. In a preferred embodiment it is believed that a minimum mass detection limit of 500 femtograms or less may be achieved through discrete optics, electronics, and an electromagnet. Also the same system can achieve a low as 0.001 cps viscosity measurement sensitivity. Preferably, integration of discrete components and further miniaturization will substantially improve the minimum detection limit, sensitivity, parallelism, and robustness of the device and will meet the challenges of label-free and parallel detection in a portable device.